Disposable container, mixing system and packaging

ABSTRACT

A bioreactor system and packaging is provided. The bioreactor system includes a vessel for housing biomaterials for processing and a support structure. The vessel includes a flexible material defining a chamber and a mixing system positioned within the chamber. The mixing system includes an agitator for imparting motion and mixing to the contents of the vessel and includes a base affixed to the flexible material at a base section of the chamber, a shaft moveably mounted in the base and extending from the base into the chamber and at least one mixing element mounted to the shaft, the shaft configured to be driven by a motor magnetically coupled to the shaft and external to the lower portion of the chamber. The support structure is connected to the mixing system such that the shaft is moveable therein and configured to cooperate with an external structure to provide support for the shaft.

BACKGROUND

Various industries are utilizing single-use or disposable systems. Theiruse continues to rapidly increase, particularly in industries, such asin biopharmaceutical industry, that require use of clean or sterilefacilities. Such disposable systems are more flexible and cost-effectivethan traditional multi-use laboratory and manufacturing facilities thatrequire extensive cleaning and sterilization processes. The componentsin disposable systems arrive sterilized and having already met tovarious regulatory requirements.

Disposable systems encompass bioreactors such as microbial bioreactorsand fermenters that may include, for example, mixing systems, in whichdisposable containers or bags are used. The containers or bags are oftenconstructed of sheets of flexible material, such as plastic, plasticlaminates or other similar materials.

Disposable mixing systems may involve containers that can be used is abioreactor system in which cells or microorganisms can grow. Thecomponents of such a mixing system can also, for example, be used toprepare buffer and media used in the bioreactor system. Containers canvary in size from a few liters up to several thousand liters in size.

As a result, there is an on-going need in biopharmaceutical developmentand manufacturing for disposable components that are sterile and easilyinstalled and utilized in, for example, a bioreactor system. There isalso a need to easily and efficiently ship or transport such disposablecomponents and have them arrive at their destination without havingtheir structure, components or sterility compromised.

BRIEF DESCRIPTION

In another embodiment, a bioreactor system comprises a vessel forhousing biomaterials for processing and a support structure. The vesselcomprises a flexible material defining a chamber and a mixing systempositioned within the chamber. The mixing system comprises an agitatorfor imparting motion and mixing to the contents of the vessel such thatbiomaterials contained within the single chamber are mixed and gasbubble circulation is increased, the agitator comprising a base affixedto the flexible material at a base section of the chamber, a shaftmoveably mounted in the base and extending from the base into thechamber and at least one mixing element mounted to the shaft, the shaftconfigured to be driven by a motor magnetically coupled to the shaft andexternal to the lower portion of the chamber. The support structure isconnected to the mixing system such that the shaft is moveable thereinand configured to cooperate with an external structure to providesupport for the shaft.

In another embodiment, a packaging for storage and transport of abioreactor system, the bioreactor system having a vessel comprising aflexible material defining a chamber and a mixing system disposed in thechamber, the mixing system including a base and a shaft rotatablymounted in the base. The packaging comprises a frame and a supportstructure. The frame comprises a base member including a cavityconfigured in size to have the mixing system base securely positionedtherein, vertical support members connected to the base member and crossmembers connecting adjacent vertical support members. The supportstructure is connected to the frame and configured to be connected tothe shaft of the mixing system.

In another embodiment, a bioreactor system and a packaging for storageand transport thereof comprises a bioreactor system, a packaging and asupport structure. The bioreactor system includes a vessel and a mixingsystem. The vessel is for housing biomaterials for processing andcomprises a flexible material defining a chamber. The mixing system ispositioned within the chamber and comprises an agitator for impartingmotion and mixing to the contents of the vessel such that biomaterialscontained within the chamber are mixed and gas bubble circulation isincreased. The agitator includes a base affixed to the flexible materialat a base section of the chamber, a shaft moveably mounted in the baseand extending from the base into the chamber, at least one mixingelement mounted to the shaft and a hub in which the shaft is rotatablypositioned, the shaft configured to be driven by a motor magneticallycoupled to the shaft and external to a lower portion of the chamber. Theflexible material also including a plurality of orifices and tubingsections having first and second ends, each orifice connected to thefirst end of one of the plurality of tubing sections that extends fromeach opening into the vessel's chamber and the second end is connectedto the hub, the connection of the orifice to the first end of the one ofthe the plurality of the tubing sections and of the second end of theone of the plurality of the tubing sections to the hub are capable ofsubstantially preventing fluid leakage. A packaging encloses thebioreactor system and includes a frame. The frame includes a base memberincluding a cavity configured in size to have the mixing system basesecurely positioned therein, vertical support members connected to thebase member and cross members connecting adjacent vertical supportmembers. The support structure includes a plurality of rods having firstand second ends connected to the hub of the mixing system at the firstend and connected to the frame at the second end to cooperate with theframe to provide support for the shaft, each rod positioned in one ofthe plurality of tubing sections of the flexible material.

Further suitable embodiments of the invention are described in thedependent claims.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features, aspects, and advantages of the presentinvention will become better understood when the following detaileddescription is read with reference to the accompanying drawings in whichlike characters represent like parts throughout the drawings, wherein:

FIG. 1 is a top perspective view of a bioreactor vessel;

FIG. 2 is a top perspective view of a stabilization hub;

FIG. 3 is a bottom perspective view of a base of an impeller assembly;

FIG. 4 is a top perspective view of an agitator;

FIG. 5 is a top perspective view of an open frame structure;

FIG. 6 is a top perspective view of a base member of an open framestructure;

FIG. 7 is a top perspective view of a slide clip;

FIG. 8 is a top perspective view of another open frame structure;

FIG. 9 is a top perspective exploded view of a packaging structure;

FIG. 10 is a top perspective exploded view of another packagingstructure;

FIG. 11 is a top perspective exploded view of yet another packagingstructure; and

FIGS. 12A and 12B are front perspective views of a bioreactor vessel andopen frame structure.

DETAILED DESCRIPTION

A description of preferred embodiments of the invention follows. It willbe understood that the particular embodiments of the invention are shownby way of illustration and not as limitations of the invention. At theoutset, the invention is described in its broadest overall aspects, witha more detailed description following. The features and other details ofthe compositions and methods of the invention will be further pointedout in the claims.

In the process of microbial fermentation, cells may have a shortdoubling time and as a result of their rapid growth, they consume moreoxygen and generate more heat than other mammalian cell applications. Asa result, systems that support such an application may include abioreactor comprising a bag of flexible material with an agitatortherein that utilizes a larger agitator motor to drive the agitator thatincludes multiple impellers mounted to a longer impeller shaft capableof delivering the required power to the fluid. Such a long impellershaft may need to be stabilized toward the top end of the shaft througha mechanism that connects the tank wall to the impeller shaft inside thebag. The agitator may be driven, for example, through a magneticcoupling with the drive head. The high gas flows within the fermentornecessitate larger filters and a condenser system to preserve the lifeof the exhaust filters and reduce the volume loss in the bioreactor. Theheat transfer surface area is maximized with a jacketed door thatresults in both high heat transfer surface area and makes baginstallation easier.

The present disclosure relates to a vessel (also herein referred to as acontainer), packaging for the vessel and the vessel and packagingtogether. The vessel can be a collapsible bag that can perform the roleof a container as part of a bioreactor system such as microbialbioreactors and fermenters. The vessel that can be used, for example, asa container in which cells or microorganisms can grow or a container inwhich liquid constituents utilized in the bioreactor system are preparedand/or stored, such as buffer and media. The bag can be of any size. Inone embodiment the collapsible bag may be selected from a twodimensional bag, a three dimensional bench top bioreactors bag and abioreactor, all of which may be sterile and may be disposable or singleuse. In another embodiment of the invention, the bag is a single use,flexible, nonporous bag. In yet another embodiment of the invention, thevessel can include means for mixing the contents thereof that may bedesirable and packaging for the vessel to provide safe and effectivetransport thereof and, if needed, maintain its sterile status.

FIG. 1—are examples of containers according the present invention.

The skilled person realizes however that for example the vessel orcontainer 100 shown in FIG. 1 may have another form or be of anothertype as long as the container comprises a side wall, top and bottom,that comprise a flexible material that are joined together to define thecontainer with an interior compartment for keeping a fluid and/or gasinside the container. The vessel may have a volume of from about 10 toabout 5000 liters, from about 10 to about 2000 liters preferably. Thevessel may also include an internal support structure that cooperateswith the vessel. The vessel may also include a flexible containerincluding an agitator (i.e., mixer) to impart motion to the contentsthereof during use as shown in FIG. 1. The support structure may alsocooperate with packaging in which the container is housed for transportand delivery it place of use.

The flexible material used in the present invention include materialthat can be easily bent without breaking and may have a thickness ofless than 1 mm, suitably of from about 0.005 mm to about 0.7 mm, andpreferably of from about 0.01-0.5 mm depending on the size and form ofthe container or bag. The flexible material may also have a flexuralmodulus according to ASTM D790 of less than 2000 MPa. The flexibility ofsuch material may also be defined by the thickness of the material,i.e., the thinner the material the more flexible the material. However,two different materials of equal thickness may have differentflexibility due to the differences in flexural modulus of the materials.Examples of other parameters typically used for such films are tensilestrength of from about 14 MPa to about 18 MPa and elastic modulus ofabout 370 MPa.

The flexible material may be a polymeric film material and can include amono layer material or a laminate comprising two or more layers. Theflexible material comprises at least one layer of a polymeric filmmaterial having thermoplastic properties. The polymeric film materialmay be sterilizable and preferably gamma radiation resistant in that itsubstantially retains its properties after exposure thereto. Suitablematerials may be conventional polymeric film materials used in thepackaging industry, preferably, for example, mono layer or multi-layerPE (polyethylene), ULDPE (Ultra Low Density Polyethylene), LLDPE (LinearLow density Polyethylene), EVOH (Ethylene Vinyl Alcohol) and PA(polyamide). Such film material may also be a laminate film constructionthat includes one or more polymeric materials or the film material mayinclude, for example, a multi-layer coextruded polyethylene film, suchas ULDPE/EVOH/PE/PA. Such a laminate film may be also include two ormore material layers, each of the material layers being differentthermoplastic materials having different melting points. The flexiblematerials included here are only meant to be examples of suitablematerials. Any flexible material with thermoplastic properties whichfulfill the necessary requirements can be used. Preferably, the flexiblematerial includes those used in biotech applications such aspolyethylene (PE) with EVOH gas barrier with PE being the inner layerand, thus, in product contact with the contents thereof.

The support structure comprises metal (for example steel or stainlesssteel) or other rigid or semi-rigid material is meant to include amaterial which is unbending or may be slightly bent, i.e. may beslightly flexible and/or has elastic properties, and can be polymericmaterial. The support structure is intended to impart separation betweenthe flexible material and the agitator to, for example, maintain theintegrity of the flexible material and reduce the opportunity for theagitator to contact and/or damage the flexible material. The flexuralmodulus of the rigid material may be greater than 200 MPa according toASTM D790. The flexural modulus value of the rigid or semi-rigidmaterial may be overlapping with the flexural modulus value of theflexible material, however, the rigidity of the rigid or semi-rigidmaterial may also be affected by the thickness of such material. Therigid material can have a thickness of at least about 1 mm with no upperlimit for the thickness of the rigid material. The rigid or semi rigidmaterial should also be substantially dimensionally stable and ispreferably moldable. Examples of such suitable materials include lowdensity polyethylene materials; high density polyethylene materials;polyamide; and polypropylene as well as composite materials including apolymer matrix, such as polyester, vinyl ester, polyamide polypropyleneor other moldable polymer materials. The polymer material preferably hasthermoplastic properties and can be sterilized and preferably resistsgamma radiation, i.e. it substantially retains its properties aftergamma radiation. The support structure parts comprising rigid orsemi-rigid material can be, for example, vacuum formed or molded, forexample, by injection molding.

The seal between the separate sections of flexible material can beobtained by several means. The seal should be fluid-tight so thatsterile conditions inside the container can be maintained. The seal canbe obtained by means of an adhesive, by heat-sealing or by using bothheat-sealing and adhesive.

The adhesives used in the adhesive seal are preferably medical gradeadhesives. The adhesives can be for example hot-melt adhesives,UV-curable adhesives or solvent-based adhesives. The hot-melt adhesivesused should preferably have a lower melting point than the flexible filmmaterial so that the flexible film does not melt when the hot-meltadhesive is applied to the material. Examples of adhesives are forexample epoxy- or silicone-based adhesives, such as MasterBond X17 and3M DP8005. Further, for example, adhesive tape could be used.

The heat seal is obtained by bringing the flexible material in contactwith heat, so that the thermoplastic component in the material melts andprovides the heat seal. The heat seal may be obtained by any suitablemanner, which are per se known to the skilled person, for example, hotair welding, conventional heat mold sealing, impulse heat sealing orultrasonic welding.

FIG. 1 shows an exemplary vessel or container 100 comprising flexiblematerial as well as within the vessel a support structure and means foragitating or mixing the contents of the container. The vessel includes afront panel 102, a back panel 104, a bottom panel 106 and side panels108. Each side panel 108 may comprise sections 110, 112 and 114.Sections 110, 112 and 114 may be separate from bottom panel 106, frontpanel 102 and back panel 104, respectively and sealed along seams 116,118 and 120 respectively or selectively integral to bottom panel 106,front panel 102 and back panel 104, respectively and folded along seams116, 118 and 120 respectively. In one embodiment sections 110, 112 and114 are integral to one another and in another embodiment, sections 110,112 and 114 are sealed along seams 122, 124 and 126. Front panel 102 andback panel 104 may be sealed to bottom panel 106 along seams 128 and130, respectively. Another alternative is for front panel 102 andsections 112 and 113 to be integral, back panel 104 and sections 114 and115 to be integral and bottom panel 106 and sections 110 and 111 to beintegral, with each of the integral portions connected via adjacentseams. Sections 111, 113 and 115 make up side panel 108 on the left sideof the figure. Front panel 102 and back panel 104 may be sealed togetherto form a top seam 130 of the container, for example, a weld seam. Topseam 130 may also include an aperture 132 or other means to hang, liftor otherwise provide upper support to the vessel in cooperation with anexternal support and/or lifting structure such as a hoist or winch (notshown).

The front panel 102, back panel 104 and bottom panel 106 may alsoinclude orifices 134 suitable to accessing the interior of the container(e.g., an input port, an exhaust port, harvest ports, etc.) orinformation about the interior of the container. The orifices 134located in bottom panel 106, for example, may be used as a drain orharvest port when the container is used as a bioreactor. Suitableconnectors can be incorporated with orifices 134 in order to attach, forexample, connectors such as, barbed tubing fitments (ports) that can beheat welded to the flexible material. Such connectors may be used toattach, for example, fluid conduits (e.g., an input conduit, an exhaustconduit, a harvest conduit, etc.) filters, probes and sensors that maybe in turn attached to tubing (for example, flexible tubing) or in thecase of probes and sensors may be stand alone or be connected to systemsthat can collect information obtained by the probe or sensor. Alsoincluded in the container is an agitator for imparting motion and mixingto the contents of the container when it is in use. The agitator mayinclude an impeller 136 which will be described in more detailsubsequently. The container may also include a support structure 138 tostabilize, impeller 136. The support structure 138 may include astabilization hub 140 that surrounds the impeller 136 and permits motionof the impeller 136 therein. The stabilization hub 140 may be connectedto rods 142. By rod is meant a slim substantially cylinder-shaped shaftconstruction, which may be hollow or solid and is made of rigid orsemi-rigid material. Each rod 142 is enclosed in tubing 144 that may bemade of the same or different flexible material as the container. Eachof the tubing 144 extends from orifice 146 to which it is attached by,for example, sealing to the stabilization hub 140 to which it is alsoattached to prevent fluid leakage from inside the container. Each sidepanels 108 may also include a tab 148 with an aperture for attaching,for example, a hook in order to lift container 100. For example, theapertures in tabs 148 can aid in the installation of the container 100into a bioreactor tank. A latched S-hook may be inserted into each ofthe two apertures of tabs 148, the S-hooks connected to a sling thatallows an operator to lift the bag when installing into the bioreactortank. Once inside the tank, an S-hook is inserted through aperture 132in top seam 130 in order to lift the remaining portion of the bag to thetop of the bioreactor tank.

An embodiment of the stabilization hub 140 in FIG. 1 is shown in FIG. 2.FIG. 2 includes the impeller shaft 200 which is rotatably positioned instabilization hub 202. Stabilization hub 202 includes a collar 204 andconnectors 206 equally spaced around the circumference of collar 204.Although the embodiment of FIG. 2 includes 3 connectors 206 forincorporating 3 rods into stabilization hub 202, that number is onlymeant to be exemplary. Preferably, at least 3 rods are connected tostabilization hub 202. Each of the connectors 206 may include a rodaperture 208 into which a rod, similar to rods 142 in FIG. 1, is slidinto position and a barb 210 over which tubing, for example, similar totubing 144 in FIG. 1, is slid over in order to prevent the tubing fromcoming off and sealing the tubing to prevent fluid leakage from insidethe container.

FIG. 3 shows an exemplary bottom 300 of the impeller assembly 301 thatis positioned closest to the bottom panel 106 in FIG. 1. Impellerassembly 301 includes an impeller base 302 with a lip 304, the latterwhich is attached to the flexible material of the bottom panel 106 inFIG. 1. This molded impeller base is thicker than the flexible materialthat makes up the envelope of the container and is made of rigid orsemi-rigid material, for example, high density polyethylene. The bottom300 of the impeller assembly 301 includes an assembly that permitsrotation of the impeller in impeller base 302, for example, containingceramic bearings and a part called a bearing carrier which clips on tothe impeller base and keeps the impeller positioned with respect to theimpeller base. The bearing assembly at the bottom of the impellerassembly 301 allows the impeller to rotate about the impeller axis whensecured to the molded impeller base 302 but is prevented from moving upor down along the impeller axis toward or away from the impeller base.The molded impeller base 302 is attached to the flexible material by,for example, heat welding the lip 304 of the molded impeller base 302 tothe flexible material.

The structure connected to, for example, the stabilization hub 140 inFIG. 1, e.g., the rods 142, should impart separation between theflexible material and the agitator to, for example, maintain theintegrity of the flexible material and reduce the opportunity for theagitator to contact and damage the flexible material. The stabilizationhub 140 may be positioned anywhere along the length of the impeller, butpreferably above the middle of the length of the impeller, morepreferably above ⅔ from the end of the impeller assembly adjacent thebottom panel 106 in FIG. 1.

FIG. 4 shows an exemplary agitator comprising an impeller and drivemechanism for the agitator. The impeller 400 includes a shaft 402 and atleast one mixing element 404. The mixing element 404 comprises, forexample, a collar 406 which is fixed to impeller shaft 402 and at leastone blade 408 fixed to the collar 406. Blade 408 can be of a suitablesize, shape and angular position relative to the axis of impeller shaft402 to provide agitation to a surrounding fluid upon rotation ofimpeller shaft 402 and the resulting movement of mixing elements 404.The impeller shaft 402 is connected to an impeller hub housed in animpeller assembly, the latter housed in a molded impeller base 410 suchthat the impeller shaft 402 is freely rotatable within the impellerassembly around the axis of the impeller shaft 402. In this exemplaryembodiment, molded impeller base 410 is secured to the flexible materialof a base panel 412, as described previously. The impeller hub isengaged with a drive mechanism 414 positioned adjacent molded impellerbase 410 on the opposite side of the flexible material of base panel412. The drive mechanism 414 includes a housing with a motor therein,the motor connected to a motor hub, the latter being freely rotatable.The positioning of the drive mechanism 414 relative to molded impellerbase 410 and impeller assemble and impeller hub house therein is suchthat magnets included in the impeller hub intereact with the motor andmotor hub of drive mechanism 414 and permit the motor to drive theimpeller hub through magnetic attraction and, as a result, drive theimpeller shaft 402 and mixing element 404 attached thereto.

The packaging for the vessel or container is designed to provide supportand protection to the container and the components thereof including theflexible material, impeller and support structure. For example,packaging structure is provided to hold and stabilize the impeller so asto minimize contact between the impeller and flexible material wheresuch contact could result in damage to the flexible material caused bythe impeller as well as hold and secure the impeller to minimizemovement of the impeller during transit that would result in damage to,for example, the impeller itself or the flexible material.

The packaging may include, for example, wall sections, connected panelsor an open frame structure including various connected support memberssuch as vertical members and cross members. Such support members andpanels can be joined using various means including interlocking (such astongue in pocket), sealing, welding or acceptable mechanical means suchas suitable mechanical fasteners, such as nut-bolt combinations, rivets,screws, nails, etc. Support members may have, for example, a square,rectangular, circular or oval cross-section.

One exemplary embodiment of packaging is shown in FIG. 5 includes anopen frame structure 500 composed of, for example, foam or other similarrigid or semi-rigid material, such as, for example, crosslinkedpolyethylene polymer including VIZION™ 4.0 and PLASTAZOTE® LD60. Theopen frame structure may be constructed of cross-link foam that is cleanroom compatible and may include multiple vertical support membersconnected with multiple cross members. In the exemplary embodiment,there are 4 vertical support members 502, 504, 506 and 508 that areconnected by 4 front cross members 512, 514, 516 and 518, 3 left sidecross members 522, 524 and 526, 3 right side cross members 530, 532 and534, and 3 back cross members 538, 540 and 542. The 4 vertical supportmembers 502, 504, 506 and 508 are connected to a base member 544 at oneend defining a bottom section with the other end defining a top section546 of the open frame structure 500. Base member 544 includes front side510, left side 520, right side 528 and back side 536.

Although 4 adjacent cross members (one front, one left side, one rightside and one back) in the embodiment are shown to connect to thevertical members at adjacent positions along the length of the verticalsupport members, it is not necessary that 4 adjacent cross members alloccupy the same positions along the vertical support members' length(i.e., they may be offset relative to the over adjacent cross members).However, it is preferred that some of the cross members be substantiallyparallel to the base member. Preferably, the top section 546 of the openframe structure may also include a central cross member 548. Centralcross member 548 may be include a tongue portion at each end that areinserted into complementary pockets in side cross members 526 and 534and affixed therein using, for example, heat welding. In one embodiment,when a container is positioned in the open frame, the top portion of thecontainer, including, for example, seam 130 and adjacent portions of theflexible material of container 100 in FIG. 1, are folded over centralcross member 548 so as to support the vessel and minimize the flexiblematerial from sagging onto the agitator housed therein. The open framestructure may also include side panels 550, 552 and 554 to provideadditional structural support and are positioned between verticalmembers 502, 504, 506 and 508 and adjacent the base member 544.

Left side cross members 522, 524 and 526, right side cross members 530,532 and 534, and back cross members 538, 540 and 542 may be integral tothe 4 vertical support members 502, 504, 506 and 508 or connected, forexample, using complementary interlocking features included in adjacentmembers (e.g., tongue in pocket) or by various sealing or adhesivetechniques. For example, front cross member 512, may include tongues 556and 558 that fit into complementary shaped pockets 560 and 562 invertical support members 502 and 508 to provide a snug fit yet can beseparated. Similar attachment means can be used for other cross member,for example, front cross members 514, 516, and 518 to vertical supportmembers 502 and 508 as well as central cross member 548 to left sidecross member 526 and right side cross member 534.

An exemplary embodiment of the base member 544 in FIG. 5 is shown inFIG. 6. FIG. 6 shows base member 600 that includes a circular cavity 602in which the bottom of an impeller (agitator) housed in the flexiblematerial container rests. Base member 600 also includes a cut-out 604(e.g., a semi-circular cut in the exemplary embodiment) on the side ofbase member 600 that faces the front side of the open structure. Oncethe impeller is positioned in the circular cavity 602, a slide clip 606is slid into slot 608 from the front side 610 of base member 600underneath cut-out 604 through a slot connecting cut-out 604 to circularcavity 602 into position in circular cavity 602 under the bottom of theimpeller. The slide clip 606 utilizes the magnetic properties of theimpeller base (that, when is use, will interact with the drive motor anddrive the motion of the agitator) to be attached to and hold the bottomof the impeller in place to stabilize the impeller base. For example, inthe event that the packing was to fall over, the slide clip with themagnetic base holds the impeller base in place and protects the bagfilm.

An exemplary embodiment of the slide clip 606 is shown in FIG. 7. Slideslip 700 includes ridges 702 and 704 with a first planar section 706between ridges 702 and 704 and a second planar section 708. The secondplanar section 708 may be positioned using the first planar section 706and ridge 702 such that the second planar section 708 is positioned incircular cavity 602 of base member 600 shown in FIG. 6 and magneticallysecures the base of an impeller positioned in the circular cavity of abase member as described previously. Therefore, side 710 of slide clip700 is slid into the slot of the base member.

The rods utilized in the support structure may the same or differentdepending on whether the container is being sterilized, shipped or inuse as a bioreactor. For example, during sterilization, the rods may bea material that does not interfere (e.g., cause shadowing) during thesterilization process, for example, polypropylene. The rods utilizedduring sterilization can be utilized during the shipping process orreplaced with other rods, such as, for example, stainless steel rods,that can be used when the container is in operation as a bioreactor.

Another exemplary embodiment of the open frame structure is composed ofsimilar rigid or semi-rigid material, including foam as shown in theembodiment of FIG. 8. Open frame structure 800 includes 4 verticalsupport members 802, 804, 806 and 808 that are connected by 3 frontcross members 810, 812 and 814, 2 left side cross members 818 and 820, 2right side cross members 824 and 826 and 2 back cross members 830 and832. The 4 vertical support members 802, 804, 806 and 808 are connectedto a base member 834 at one end defining a bottom section. The openframe structure may also include side panels 816, 822 and 828 to provideadditional structural support and are positioned between verticalmembers 802, 804, 806 and 808 and adjacent the base member 834. A topsection that includes front left angled support 836 connected tovertical support members 802, rear left angled support 838 connected tovertical support members 804, front right angled support 840 connectedto vertical support members 808 and rear right angled support 842connected to vertical support members 806. The ends of front left angledsupport 836 and rear left angled support 838 opposite to the respectivevertical members to which each is attached are connected to each otherat 844. The ends of front right angled support 840 and rear right angledsupport 842 opposite to the respective vertical members to which each isattached are connected to each other at 846. A central cross member 848is connected to angled support members 836, 838, 840 and 842 atpositions 844 and 846 as shown. As an alternative, such members andsupports may be formed to have any two adjacent elements integral withone another rather than being connected.

Although adjacent cross members (one front, one left side, one rightside and one back) in the embodiment are shown to connect to thevertical members at adjacent positions along the length of the verticalsupport members, it is not necessary that 4 adjacent cross members alloccupy the same positions along the vertical support members' length(i.e., they may be offset relative to the over adjacent cross members).Also, members are connected, for example, using complementaryinterlocking features included in adjacent members or by various sealingor adhesive techniques. Other structural details disclosed for theembodiment of FIG. 5 may also applicable to the embodiment of FIG. 8.

The packing of FIG. 9 comprises packing materials and open framestructure 900. Open frame structure 900 is configured to house anaforementioned container. Various components (e.g., feed lines, tubing,probe and sensor lines) attached to the container positioned in openframe structure 900 may be secured using various attachment meansincluding, for example, cable ties. Open frame structure 900 may becovered with, for example, one of two layers of plastic, such as about a4 mil to about a 6 mil (about 0.004 to about 0.006 inches) clearpolypropylene bag including, for example, double bagged in which eachis, for example, a polypropylene bag. The plastic covering may includean inner pouch and an outer pouch that cover the open foam frame (e.g.,a double bag enclosure). As a result of the exemplary double bagenclosure (or other multi-bag enclosure) around the open framestructure, the bagged open frame structure with the vessel helpsfacilitate easily passing of the entire assembly through a materialairlock and to a clean-room housing the bioreactor, thus minimizingdamage to the vessel due to handling. Other open frame structures can beincorporated such as the embodiment of open frame structure 500 in FIG.5 and the embodiment of an open frame structure 800 in FIG. 8.Additional packing material are shown in FIG. 9 and include a bottomcorrugate tray 902 and top corrugate tray 904 that, when assembled, arepositioned adjacent the top section 906 and base section 908 of openframe structure 900. The packing material may also include C-foldcorrugate sleeves 910 and 912 and are positioned around the area of openframe 900 that is exposed after bottom corrugate tray 902 and topcorrugate tray 904 are in position. Also shown is shipping pallet 914 onwhich bottom corrugate tray 902 may be supported and/or attached.Shipping straps (not shown) may then be used to secure the assembledopen frame structure 900 (including container, not shown), plasticcovering (if needed), bottom corrugate tray 902, top corrugate tray 904and C-fold sleeves 910 and 912 to shipping pallet 914.

Other alternative packing can include the embodiments shown in FIG. 10and FIG. 11. The embodiments of FIG. 10 and FIG. 11 are shown with anagitator and without the container in which the agitator is housed inorder to show the interaction between the agitator, support structureand packing shown in the figures. In practice, an embodiment of theaforementioned vessel of flexible material and its various componentswould be included. FIG. 10 shows packing 1000 for agitator 1002 ispositioned on base 1004 which includes a cavity in which the bottom ofan agitator is placed. Packing 1000 also includes a top section 1006, abottom section 1008 on which base 1004 is positioned, 4 side sections, 3of which are shown 1010, 1012 and 1014. The fourth side section isstructured similarly to 1010, 1012 and 1014. Side sections 1012 and 1014also include struts 1016 and 1018. Strut 1020 is connected to the fourthside section, not shown. Struts 1016, 1018 and 1020 are positionedadjacent each other and are attached to support structure 1022 via rods1024. Strut 1020 is positioned on the fourth side section similarly towhere struts 1016 and 1018 are positioned on side sections 1012 and1014. Side section 1010 may also include a strut similar in structure tostruts 1016, 1018 and 1020 and positioned similarly where struts 1016and 1018 are positioned on side sections 1012 and 1014. Supportstructure 1022 is connected to agitator 1002.

FIG. 11 shows packing 1100 for agitator 1102. Packing 1100 also includesa top section 1104, bottom section 1106 on which agitator 1102 ispositioned, 4 side sections 1108, 1110, 1112 and 1114. Support structure1116 is connected to the side sections via rods 1118. Support structure1116 is connected to agitator 1102.

In one embodiment, the container may be shipped after sterilization.With such an embodiment, unpacking the vessel may be accomplished so asto maintain the sterility of the container as shown, for example, asshown in FIG. 12A and FIG. 12B. Both FIG. 12A and FIG. 12B includevessel 1200 positioned in open frame structure 1202. After thesurrounding packing materials (e.g., double polypropylene bags referredto above) have been removed including for example, a plastic enclosurearound the open frame and cable ties used to secure various vesselcomponents (e.g., feed lines, tubing, probe and sensor lines) to theopen frame structure, the slide clip 1204 and front cross member 1206 asshown in FIG. 12A are removed. As a result, shown in FIG. 12B supportstructure rod 1208 may be removed through orifice 1210 in container1200. Support rods 1212 and 1214 may then be lifted to release them fromthe open frame structure 1200 and removed in a similar manner. Top backcross bar 1216 and front cross members 1218, 1220 and 1222 shown in FIG.12A may then be removed. Upon the completion of the removal of top backcross bar 1216, front cross bars 1206, 1218, 1220 and 1222, slide clip1204 and support rods 1208, 1212 and 1214, container 1200 can be removedfrom open frame structure 1202 with minimal compromise to its sterilecondition. Top back cross bar 1216 and front cross bars 1206, 1218 and1220 as well as the other parts of open frame structure 1202 may beconnected using, for example, tongue and pocket interlocking features.Furthermore, One of the main advantages of this packaging is that theassembly of the double bagged open frame structure with vessel thereinis clean-room compatible. Also the entire foam structure beingdouble-bagged help facilitate easily passage of the assembly through amaterial airlock and to the bioreactor clean-room. A user can,therefore, bring the assembly to the bioreactor itself before completingthe unpacking process, thus minimizing damage or sanitary compromise tothe bag due to handling. For example, features such as the removablecross-members, support rods and slide clip allow easy tool-freedisassembly and instillation at the bioreactor, which is completed bylifting the vessel from the packaging material into the bioreactor. As aresult, the vessel is maintained in a controlled protective environmentfrom the manufacturer to the point of installation and use in thebioreactor.

This written description uses examples as part of the disclosure,including the best mode, and also to enable any person skilled in theart to practice the disclosed implementations, including making andusing any devices or systems and performing any incorporated methods.The patentable scope is defined by the claims, and may include otherexamples that occur to those skilled in the art. Such other examples areintended to be within the scope of the claims if they have structuralelements that do not differ from the literal language of the claims, orif they include equivalent structural elements with insubstantialdifferences from the literal languages of the claims.

The invention claimed is:
 1. A bioreactor system comprising: a vesselfor housing biomaterials for processing, the vessel comprising aflexible material defining a flexible chamber having a chamber wall thatcomprises at least three orifices and a tubing section extending fromeach orifice into the chamber; a mixing system positioned within thechamber, the mixing system comprising an agitator for imparting motionand mixing to the contents of the vessel such that biomaterialscontained within the chamber are mixed and gas bubble circulation isincreased, the agitator comprising: a base welded to the flexiblematerial at a base section of the chamber, a shaft moveably mounted inthe base and extending from the base into the chamber, and at least onemixing element mounted to the shaft, the mixing element and the shaftconfigured to be driven by a motor magnetically coupled to the shaft andexternal to a lower portion of the chamber; and a support structurecomprising a hub engaged with the shaft above a middle of the mixingsystem relative to the base while physically connected to the flexiblematerial through the tubing sections to impart separation between thechamber and the mixing system to cooperate with an external structure toprovide support for the vessel, wherein the hub comprises a collardisposed circumferentially about the shaft, the shaft axially extendingthrough the collar on both sides of the collar, wherein the collar isspaced from the at least one mixing element along the shaft, wherein theshaft is rotatably secured within the collar of the hub, and wherein thesupport structure including the hub may be positioned in at least twodifferent locations along the length of the shaft, with a first positionfor providing support during transportation or storage and a secondposition for providing support during the operation of the reactor. 2.The bioreactor system of claim 1, wherein the base welded to theflexible material at the lower portion of the chamber is a first pointof support for the mixing system and the support structure engaged withthe shaft is a second point of support for the mixing system.
 3. Thebioreactor system of claim 1, wherein the support structure comprises: aconnector attached to the hub and configured to receive a rod andconnectable with the tubing section of the chamber wall, and a rodinserted into the connector that can be connected to a bioreactor tankor a shipping container.
 4. The bioreactor system of claim 1, whereinthe support structure further comprises: at least three connectors on acircumferential surface of the hub and equally spaced, and three rodseach inserted into each of the at least three connectors tosubstantially prevent fluid leakage from the vessel.
 5. The bioreactorsystem of claim 1, wherein the at least one mixing element includes animpeller blade.
 6. The bioreactor system of claim 1, wherein theexternal structure includes a bioreactor tank or a shipping container.7. The bioreactor system of claim 1, wherein the flexible materialincludes a plastic container or a flexible plastic bag.
 8. Thebioreactor system of claim 1, wherein the vessel includes at least oneinput port, at least one exhaust port, at least one harvest port and atleast one sensor or probe.
 9. The bioreactor system of claim 1, whereinthe tubing sections comprises flexible material.
 10. The bioreactorsystem of claim 1, wherein the hub is the sole hub, and wherein thecollar is the sole collar.
 11. A packaging for storage and transport ofthe bioreactor system of claim 1, the packaging comprising a framecomprising: a base member including a cavity configured in size to havethe mixing system base securely positioned therein, vertical supportmembers connected to the base member, and cross members connectingadjacent vertical support members; with the support structure connectedto the frame through the orifices and engaged with the shaft of themixing system in the first position.
 12. The packaging of claim 11,wherein the support structure includes a plurality of rods each enclosedin one of the plurality of tubing sections with one end of the rodsconnected to the hub and the other end of the rods protruding throughthe orifices to be connected to the frame of the packaging.
 13. Thepackaging of claim 11, further including a slide clip that is positionedin the cavity of the base member and is capable of being magneticallyattached to the mixing system base.
 14. The packaging of claim 11,wherein the frame includes four vertical support members defining afront side, a left side, a right side and a back side; four front sidecross members, three left side cross members, three right side crossmembers and three back side cross members such that an open space isdefined in the frame of a suitable size to allow the vessel to bepositioned in the open space.
 15. The packaging of claim 14, wherein thefront side cross members are elongated defining two ends and including atongue portion at each end and the vertical support members to which thefront side member is attached include a pocket of a complementary shapeto the tongue portion so as to provide a substantially snug fit when thetongue portion is positioned in the pocket.
 16. The packaging of claim11, wherein the frame includes a top section, a base section, and sides,the packaging further comprising: an external packing, the externalpacking including: a top tray that is positioned adjacent the topsection of the frame, a bottom tray that is positioned adjacent the basesection of the frame, and sides positioned adjacent the sides of theframe.
 17. The packaging of claim 16, further comprising a shippingpallet on which the bottom tray is positioned and at least one shippingstrap to secure the packaging and external packing to the shippingpallet.
 18. An assembly including a bioreactor system and a packagingfor storage and transport thereof, the bioreactor system comprising: avessel for housing biomaterials for processing, the vessel comprising aflexible material defining a chamber having a chamber wall thatcomprises at least three orifices and a tubing section extending fromeach orifice into the chamber, and a mixing system positioned within thechamber, the mixing system comprising: an agitator for imparting motionand mixing to the contents of the vessel such that biomaterialscontained within the chamber are mixed and gas bubble circulation isincreased, the agitator comprising a base affixed to the flexiblematerial at a base section of the chamber, a shaft moveably mounted inthe base and extending from the base into the chamber, at least onemixing element mounted to the shaft, and a support structure having ahub comprising a collar in which the shaft is rotatably positioned, thecollar being spaced from the at least one mixing element along theshaft, the shaft configured to be driven by a motor magnetically coupledto the shaft and external to a lower portion of the chamber; thepackaging enclosing the bioreactor system, the packaging including aframe comprising: a base member including a cavity configured in size tohave the mixing system base securely positioned therein, verticalsupport members connected to the base member, and cross membersconnecting adjacent vertical support members; wherein the supportstructure comprises a plurality of rods each having a first end and asecond end, enclosed in one of the plurality of tubing sections with thesecond end protruding through the orifices, connected to the hub at thefirst end, and connected to the frame at the second end to cooperatewith the frame to provide support for the mixing element.
 19. Thebioreactor system and packaging of claim 18, wherein the packaging andenclosed bioreactor system are contained in at least two plastic bags.20. The bioreactor system and packaging of claim 18, wherein the tubingsections comprises flexible material.
 21. An assembly comprising abioreactor system and a packaging for storage and transport thereof, thebioreactor system comprising: a vessel for housing biomaterials forprocessing, the vessel comprising a flexible material defining a chamberhaving a chamber wall that comprises at least three orifices and aflexible tubing section extending from each orifice into the chamber,and a mixing system positioned within the chamber, the mixing systemcomprising: an agitator for imparting motion and mixing to the contentsof the vessel such that biomaterials contained within the chamber aremixed and gas bubble circulation is increased, the agitator comprising abase affixed to the flexible material at a base section of the chamber,a shaft moveably mounted in the base and extending from the base intothe chamber, at least one mixing element mounted to the shaft, and asupport structure having a hub comprising a collar in which the shaft isrotatably positioned, the collar being spaced from the at least onemixing element along the shaft, the shaft configured to be driven by amotor magnetically coupled to the shaft and external to a lower portionof the chamber, the hub having a circumferential surface and at leastthree barb connectors positioned on the circumferential surface; thepackaging enclosing the bioreactor system including a frame comprising:a base member including a cavity configured in size to have the mixingsystem base securely positioned therein, vertical support membersconnected to the base member, and cross members connecting adjacentvertical support members; wherein the support structure comprises aplurality of rods each having a first end and a second end, enclosed inone of the plurality of tubing sections with the second end protrudingthrough the orifices, connected to the hub at the first end, andconnected to the frame at the second end to cooperate with the frame toprovide support for the mixing element.